Primary treatment for breast cancer includes surgery accompanied with systemically cytotoxic chemotherapy and/or locally cytotoxic radiation treatment. In recent years multiple molecular signatures of breast cancer have been identified. HER directed therapies with drugs like trastazumab can still fail as many HER-2 amplified tumors are, or become resistant to therapy. However, even the resistant tumors may still continue expressing the HER-2 receptor for targeting by alternative therapeutic methods. Another promising imaging/therapeutic target for breast cancer is the over expression of Insulin like growth factor-I receptor (IGF-IR), which can potentially affect a much larger class of patients. However, despite the emerging molecular medicine-based shift towards cancer-specific cytostatic agents, cytotoxic chemotherapy is still considered more effective against broad patient populations. Hence, the early thrust of cancer nanotechnology was focused towards the development of nanocarriers for delivering diagnostic/therapeutic payloads to improve conventional chemotherapy and minimize side effects. These approaches are not externally controlled: the inability to guarantee intracellular drug delivery often results in treatment failure and it cannot address de novo and acquired drug resistance. Alternative cancer nanotherapeutics based on the photothermal response of gold nanostructures designed to absorb near-infrared (NIR), tissue-penetrating light has exhibited near 100% efficacy in the remission of tumors: this stands as one of the most promising new technologies to emerge from nanoscience research in the past decade. We recently reported a new class of photothermally active multifunctional nanomaterials, which dramatically enhance the NIR fluorescence of weak organic dyes (50X), and provide a strong T2 weighted MR contrast. We demonstrated successful bimodal (NIR/MR) imaging and therapy of breast cancer cells with these magneto-fluorescent hybrid nanoparticles (hereafter referred as hNPs) by targeting the HER-2 receptor over-expression with trace dosage of antibody. Herein, we propose an interdisciplinary partnership between the departments within the Baylor College of Medicine and Rice University to introduce a novel plasmonics based molecularly targeted theranostic technology for the treatment of drug resistant breast cancer. The convergence of nanotechnology, bio-imaging, and medicine bring the promise of an era of nanomedicine in which agents can be tuned, tailored and targeted into simultaneous therapeutic and diagnostic (theranostic) vehicles for highly specific, personalized medicine. The specific aims of this five-year research program are: 1. Fabricate and characterize a panel of hybrid magneto-fluorescent nanoparticles for combined imaging and therapy. 2. Develop and test instrumentation for combined NIR/MRI tomographic imaging and therapy 3. Validate the multimodal theranostic instrumentation on drug resistant xenograft tumors in nude mice by targeting the HER-2 and IGF-I receptor over-expression. 4. Investigate the treatment of Her-2/IGF-I over-expressing breast cancer metastasis with image guided photothermal therapy.)) PUBLIC HEALTH RELEVANCE: In this project we will develop a near infrared optical tomography scanner to exploit plasmonically enhanced fluorescent dyes for molecular imaging. Tunable nanoshells will be designed and manufactured to enhance the yield and lifetime contrast of near infrared fluorescent dyes. The developed system and methods will be validated on a clinically relevant Swine based animal model for detecting lymph node locations in three dimensions, following microdose intradermal injections of nanoshell conjugated fluorescent dyes. In addition, a preclinical study will be conducted to demonstrate early stage detection of pancreatic cancer in an orthotopic animal model with a molecularly targeting antibody-nanoshell-fluorescent dye based agent.